For over 70 years, researchers have sought to understand of how dietary restriction (DR) extends the lifespan of mammals. In recent years, extra copies of the SIR2 gene have been shown to extend the lifespan in organisms such as baker's yeast, C. elegans and Drosophila, apparently by mimicking DR. Knowing whether the mammalian homolog of SIR2, SIRT1, can mimic DR physiology and extend the lifespan of mammals is one of the most important questions in the aging field today because it could simultaneously lead to new understandings about mammalian aging, about DR physiology, and could lead to drugs that effectively treat the major diseases of society including cancer, neurodegenerative disorders, heart disease and diabetes, not to mention significantly increasing our lifespan. In collaboration with experts in the field, we have begun to answer this question by generating a conditional and tissue-specific SIRT1 overexpressing mouse (SIRT1-Tg) and by treating mice with a SIRT1 activating compound (STAC) called resveratrol. We initiated these experiments over 18 months ago and have generated a large body of data to support this application. We show that resveratrol is mimicking DR in our mice, based on a wide variety of physiological and biochemical changes, including lowering blood glucose, insulin/IGF-1, suppressing cancer, protecting against Alzheimer's and Huntington's disease, depleting fat, and preventing memory loss. At the gene expression level, we show that most of the pathways altered by resveratrol are also altered by a low calorie diet, including IGF-1/mTOR signaling, glycolysis, fatty acid synthesis, electron transport and beta oxidation. We show that SIRT1 causes effects similar to resveratrol. The SIRT1-Tg mice have lower insulin and IGF-1 and show increased resistance to spontaneous colon cancer using the APCmin model. We will explore the mechanism by which SIRT1 and resveratrol suppresses colon cancer, which appears to be though b-catenin signaling. The study is at a stage where there is no doubt important insights will be gained about DR and diseases of aging, such as diabetes, neurodegeneration and cancer. Many of the mice are housed at NIH, not at Harvard, as a cost-saving measure. I request funds to continue this study so that we can test these animals and the SIRT1-Tg for traits seen in DR animals including cytokine alterations, resistance to toxins, increased disease resistance, and slower aging. A conditional SIRT1 knockout mouse has been obtained to understand mechanisms of action by testing whether SIRT1 is required for DR and resveratrol to prevent diabetes, suppress cancer and extend lifespan, and by dissecting the pathways we have already identified as candidates for mediating the health benefits we have seen in our resveratrol-fed and transgenic mice. [unreadable] [unreadable] [unreadable]